Reviews on Recent Clinical Trials - Volume 7, Issue 4, 2012

The Authors review and critically discuss the most recent published evidence on treatment of mild-moderate ulcerative colitis both in the induction and maintenance of remission. Evidence on each drug is introduced by the related statement of ECCO guidelines. A brief introduction on disease classification and the need of standardizing indexes of clinical and endoscopic activity is also provided. Concluding remarks stress the heterogeneity of available studies both in the selection of patients and the outcomes evaluated and suggest the development of an international consensus in setting standards which will allow studies' results to be compared and combined to produce high quality clinical recommendations.

Maintenance of medically induced remission is a clinical challenge in Crohn's disease (CD), since it is a chronic disease and that often occurs in young people. The introduction of immunosuppressors and biologics has significantly improved the management of these patients, however efficacy and safety of these treatments in the very long term still needs clarification. Furthermore, scientific research is driven more into new drugs to induce remission rather then maintenance.

Randomized controlled trials (RCTs) are the gold standard method for developing evidence-based medicine in inflammatory bowel disease (IBD). Methodological problems in RCTs in IBD concern different aspects such as the definition of the study population due to the extreme variability of patients with IBD, the indices of disease activity, a clearly defined outcome, the environmental risk factors (i.e smoking behaviour) that may influence the randomization, the heterogeneous placebo rate of remission and the different statistical methods used to analyze the results. It is important that trials are designed efficiently, done well and complement clinical practice with a careful subject selection, standardization of disease activity indices, and precise outcome measurement in order to continue the improvement of the IBD research process.

Many trials focused on the treatment of active luminal Crohn's disease (CD) have been published in literature. A critical reevaluation of the main trials regarding the use of 5-ASA derivates has shown a not significant benefit of such molecules in treating CD and, as a consequence, the European Crohn's and Colitis Organization's (ECCO) therapeutic statements highlight that 5-ASA should be considered clinically no more effective than placebo for active disease. The main evidence regarding the efficacy of conventional steroids as inductive therapy in active CD is still based on the old but fundamental Cooperative studies which can be considered at low risk for biases in spite of the date of publication. Most probably these RCTs will remain unsurpassed. Current data do not support the use of antibiotics for active luminal CD as primary therapeutic strategy in view of very conflicting results. In accordance with these conclusions current guidelines dot not suggest this kind of treatment in active CD. Even if frequently used, data about the role of conventional immunosuppressors for the therapy of active luminal CD ara scanty. Azathioprine/6-MP should be no more considered as remission-inductive agents for active CD while methotrexate could be considered an effective therapeutic option in inducing remission in this setting particular setting. A number of clinical trials are available about the use of anti-TNF alpha agents (infliximab, adalimumab) in active luminal CD. Both drugs are surely effective in inducing remission even if safety and economic concerns should be better considered and investigated.

Crohn's disease can be complicated by the development of fistulas, 54% of which involve the perianal region. The presence of perianal fistulas predicts a disabling course of Crohn's disease. The treatment of complex perianal disease is difficult and the chance of complete fistula healing is no more than 50%. The best management of this condition is a combining medical and surgical therapy. Studies which evaluated the efficacy of medical treatments in this setting are small, open label and considered the efficacy on perianal disease as a second outcome or as the result of a subgroup analysis. In the few available trials the efficacy outcomes were evaluated by the Fistula Drainage Assessment but recently it was observed that inflamed fistula tracks often persist, despite the apparent closure of external orifices. Up to now the most strongly evaluated medical treatments for perianal Crohn's disease are the anti-TNFα antibodies. In presence of complex fistulas they are considered the first choice of medical treatment, in combination with surgical therapy. Antibiotics and immunomodulators have not been demonstrated to result in sustained closure of fistulas in Crohn's disease. Their use is recommended as a second line medical treatment. The use of tacrolimus and thalidomide is limited by its side effects. A few evidences support the use of methotrexate and cyclosporine but they are insufficient.

Pouchitis is the most common complication of Proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). The diagnosis of pouchitis requires the presence of symptoms, together with characteristic endoscopic and histological abnormalities. The exact cause of pouchitis is not known. Whereas ‘acute’ pouchitis can be treated rapidly and successfully in the majority of patients, “refractory” and ‘chronic pouchitis’ remain therapeutic challenges to patients and physicians. Metronidazole and Ciprofloxacin budesonide enemas and oral probiotic therapy with VSL#3 all appear to be effective therapies for acute and/or chronic pouchitis. The medical therapy of pouchitis remains largely empiric, and additional multicenter, randomized, double-blind, placebo-con- trolled, dose-ranging trials are needed. In future trials, treatment indications such as active acute or chronic pouchitis and maintenance of remission for acute or chronic pouchitis should be clearly defined.

Most patients with Crohn's disease will require surgery during the course of their disease. However, surgery is not curative and post-operative recurrence is quite inexorable. One year after resection up to 80% of patients have new lesions at the neo-terminal ileum and after 10 years approximately 50% of patients will experience recurrence of symptoms and 35% will need further surgery. Prevention of post-operative recurrence has, therefore, a central role in the management of Crohn's Disease. Several drugs have been evaluated to decrease the risk of both endoscopic and clinical recurrence but the overall results are largely not impressive. Among the different drugs evaluated, mesalazine, antibiotics (metronidazole and ornidazole), thiopurines and anti-TNFα antibodies have been shown to be effective whereas budesonide, probiotics and interleukin 10 are not effective. This review focuses on the actual evidence on the prevention of postoperative recurrence: randomised controlled trials and meta-analyses are critically reviewed and discussed with particular attention to the methodological aspects.

Intravenous steroids are considered the mainstay of treatment in patients with severe ulcerative colitis. Several randomized controlled trials have been designed to evaluate drugs that, as an adjunct to intravenous steroids, could obtain a clinical response and avoid colectomy in patients who do not respond to corticosteroids. For steroid refractory patients, cyclosporine and infliximab seem to be an effective alternative to colectomy in the short term, but more data are needed to evaluate if they can prevent colectomy also in the long term. Although there is no evidence from the published trials that antibiotics as adjunctive therapy may have an additional benefit, therapeutic protocols for severe ulcerative colitis generally include antibiotics for patients with signs of toxicity, or with worsening of symptoms despite the medical treatment. No additional benefit over steroids has been shown from bowel rest. Moreover, as bowel rest deprives the colonic enterocytes of the short-chain fatty acids vital to their metabolism and repair, it may even be harmful. Conflicting results have been published on heparin as primary treatment of severe ulcerative colitis; at the present time there is no evidence supporting its use. Although “steroid-free” clinical remission is, at this time, the most important end point of clinical studies in inflammatory bowel disease, only few data are available in steroid dependent colitis patients. Azathioprine seems to be effective in inducing steroid-free remission.

The aim of this study was to evaluate the efficacy of ozone therapy in the treatment of 50 patients with peripheral vestibulocochlear syndrome. Ozone was injected in the cervical region C2-C3, for 20 sessions. Evaluation criteria was based in the evolution of nystagmus, tinnitus, hearing loss and vertigo. Also, oxidative stress parameters were measured. Results demonstrated that patient improvements, according to vertigo, hearing loss, tinnitus and nystagmus, were of 90, 80, 65 and 100%, respectively. These patients were initially under condition of systemic oxidative stress, however, at the end of the study a redox balance was achieved. No side effects were observed.

This paper addresses a clinical hypothesis detected by the method of range regression, a new statistical method portraying the clinical response via the range of an explanatory variable. For patients with iliofemoral deep venous thrombosis, it has long been clinically suspected that residual thrombus affects the quality of life after catheter-directed thrombolysis. However, such important medical experience has not been validated or scientifically quantified by experimental or observational data. In clinical practice, this association may directly affect the duration of thrombolytic therapy or other attempts at clot removal. In this study, we develop a new regression model to identify how the quantity of clot lysed affects the clarification of chronic venous disease after catheter-directed thrombolysis (a correlated index on postthrombotic quality of life). Bridging clinical insight with statistics by means of medical records of 62 IFDVT patients, the new method reveals that residual thrombus significantly and substantially affects post-thrombotic clarification of chronic venous disease. The conclusion of the new method is confirmed by a conventional logistic regression method when 50% thrombus removal is treated as a categorization threshold. This new approach is applicable to analyze other clinical or medical variables on the treatment of venous diseases.